Control of Elemental Impurities

The European Pharmacopoeia (Ph. Eur.) traditionally collaborates closely with European regulatory authorities. The Ph. Eur. Convention specifies that member states nominate their delegates for the Ph.Eur. Commission, the governing body of the Ph. Eur.Currently, all delegations include at least one representative from a health authority who normally also serves as head of the delegation. It is not surprising, therefore, that the texts of the Ph. Eur. are much aligned with regulatory developments in its 37 member states. This is a true benefit for users, as it ensures that compliance with the legally binding Ph. Eur. standards makes it easier to obtain marketing authorizations from competent authorities throughout the continent.

Changing the strategy
The decision of the Ph. Eur. Commission to revise its strategy regarding control of metal catalyst or metal reagent residues is a recent example of the consistency between the approaches of European licensing authorities and the Ph. Eur. This revision followed a discussion at the Committee for Medicinal Products for Human Use (CHMP), the leading EU scientific committee involved in assessing marketing authorization applications coordinated by the European Medicines Agency (EMA).

In 2008, the CHMP adopted a EU guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000). CHMP’s Safety Working Party developed this guideline in close collaboration with the Joint CHMP/CVMP Quality Working Party. It defines specification limits for 14 metal elements according to their route of administration and came into effect in September 2008 for new drug products while defining a five-year transition period for existing drug products. When it was adopted, it was intended that the requirements of the guideline would apply to existing products by September 2013 at the latest.

Revising compendia tests on heavy metals
The current compendia tests on heavy metals (Chapter 2.4.8 of the Ph. Eur.) have been criticized by users for not being adequate and state-of-the-art for the control of all relevant metal elements. A revision of these tests, therefore, has been included on the work program of the Ph. Eur. Commission. However, as methods and specifications are linked, the commission felt it important not to proceed with a revision of the chapter until limits had been harmonized and agreed upon. At the same time, to support the implementation of the CHMP guideline in line with what has been done in the past (e.g., related to the International Conference on Harmonization [ICH] guidelines on control of impurities in active substances [ICH Q3A] or on residual solvents [ICH Q3D]), the Ph. Eur. Commission decided to introduce the CHMP guideline as a general chapter for information only, as is the case for all general chapters that are not referred to by a monograph. This was done in Ph. Eur. Supplement 7.7, which came into effect in April 2013. As the final step, the commission decided at its 145th session in March 2013 to introduce a reference to this general chapter in the general monograph “Substances for pharmaceutical use” (2034), which would make the requirements of the general chapter mandatory for all substances used in the production of medicines for the European market, regardless of whether or not they are covered by an individual monograph in the Ph. Eur.

At the international level, in October 2009, the ICH Steering Committee endorsed a concept paper on the development of a harmonized ICH Guideline for Elemental Impurities, a project known as ICH Q3D. Step 2b of this guideline was completed in June 2013, and the document is currently published in the EU for comments until December 31, 2013. While the limits defined in the CHMP guideline referred to previously have been used as a basis for ICH Q3D discussions, the latter has a different scope in terms of both geography (which is normal for an ICH guideline) and the elements covered, notably in that it defines limits for the so-called “big four” contaminants arsenic, cadmium, mercury, and lead among the 24 elements it deals with. At present, these are not covered by the current CHMP guideline. In addition, certain limits proposed in the current version of the ICH document differ from those that have already been implemented via the CHMP guideline in Europe. For some of the elements the limits are wider (e.g., chromium, nickel, and platinum), while for others they are stricter (e.g., copper, molybdenum, and vanadium). A certain degree of disharmony between the current European and the future ICH guideline should be noted.

Harmonization
Being committed to international harmonization, European regulators and the Ph. Eur. Commission have stated from the inception of the ICH guideline that they would update their respective requirements in line with the outcome of the discussions at the ICH level. This means that the CHMP guideline would be replaced by the ICH guideline once the CHMP adopts the latter, which according to EU procedures is the final step in the implementation in the EU of an ICH guideline adopted by the ICH Steering Committee. The Ph. Eur. Commission would do the same for its general chapter on metal catalyst or metal reagent residues (Chapter 5.20). The Ph. Eur. has always been clear that it will keep the European requirements for the time being and revise the respective chapter to align them with the ICH requirements once the discussions at the ICH level have been finalized. This strategy contrasts with what has been announced by the United States Pharmacopeial Convention, which has been developing its own specification limits for elemental impurities in parallel with the ICH discussions.

In the meantime, the ICH document has reached step 2b, but some of the limits are different from the ones previously defined by European regulators and applied by the Ph.Eur. Normally, according to the CHMP guideline, the latter requirements should have become applicable to existing products as well in September 2013. Likewise, the Ph. Eur. would have made these requirements legally binding for all substances for pharmaceutical use as of Supplement 8.1, which will come into force in April 2014. This would have created further disharmony for industry. To avoid this, the CHMP decided at its July 2013 meeting to postpone the application of its guideline to existing products and to await the outcome of discussions at the ICH level before taking any further measures. As an integral part of the European regulatory network and to ensure continued consistency between the policies applied by regulatory authorities and the pharmacopoeia, the Ph. Eur. Commission has decided to defer the addition of a reference to the general chapter in the general monograph “Substances for pharmaceutical use.” This should not be confused with the decision of the USP Executive Committee of Council of Experts to postpone the implementation of its respective General Chapters <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures, which was made for different reasons.

The decision to postpone the implementation of the full scope of the CHMP Guideline on the specification limits for residues of metal catalysts or metal reagents made by the CHMP and the Ph. Eur. Commission are an excellent example of the benefits of close collaboration between regulators and the pharmacopoeia authority, not only for themselves, but also for industry. Just imagine the situation if one party had decided to defer the extension of the scope of the CHMP guideline to existing products while the other had made them mandatory.

Susanne Keitel, PhD

About the Author
Susanne Keitel, PhD, is head of the European Directorate for the Quality of Medicines of the Council of Europe. EDQM is responsible for the European Pharmacopoeia.